Even after TNFi cessation, remission was 34% higher

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In early rheumatoid arthritis, initial therapy with methotrexate (MTX) + a tumor necrosis factor-inhibitor (TNFi) is associated with a higher chance of retaining low disease activity and/or remission, even after discontinuing the TNFi.

Note that these conclusions were from a small Swedish meta-analysis of a few studies, with differing protocols, including varying dosages of methotrexate, and where eligible patients were less diverse than those in daily practice.

Starting initial treatment for early rheumatoid arthritis (RA) with methotrexate plus a tumor necrosis factor (TNF) inhibitor was associated with a greater likelihood of maintaining low disease activity and/or remission compared with methotrexate alone -- even after discontinuation of the biologic, according to a small Swedish meta-analysis in RMD Open.

Despite substantial heterogeneity among the six analyzed randomized controlled trials, published from 2004 to 2014, the researchers found pooled relative risks for achieving low disease activity during induction and clinical remission after anti-TNF cessation of 1.41 (95% CI 1.05 to 1.89) and 1.34 (95% CI 0.95 to 1.89), respectively.

At the end of the induction phase, the pooled relative risks for low disease activity and remission were 1.70 (95% CI 1.21 to 2.38) and 1.67 (95% CI 1.42 to 1.95), respectively, confirming the superior effectiveness of the combination over monotherapy.

"If these results are confirmed, treating early RA with methotrexate plus a TNF inhibitor followed by maintenance with methotrexate alone may be a reasonable strategy despite high initial costs," wrote Sharzad Emamikia, PhD, from Karolinska University Hospital in Stockholm and colleagues.

They cautioned, however, that definitive biomarkers are needed to identify subsets of patients who will derive lasting benefit. "Future randomized clinical trials confirming the 'induction-maintenance' approach may lead to a paradigm change in the treatment of early RA," Emamikia and associates wrote.

The meta-analysis involved early RA patients who were naive to biologics and conventional synthetic disease-modifying antirheumatic drugs (DMARDs). They had had clinically active disease for no more than 1 year and symptoms for no more than 2 years.

The primary outcome was the proportion achieving a Disease Activity Score in 28 Joints of less than 3.2 for low disease activity and of less than 2.6 for remission at follow-up, which ranged from 12 to 76 weeks.

During the maintenance phase, the low disease activity rate after discontinuing the biologic in the methotrexate plus anti-TNF group ranged from 33% to 83% and the remission rate ranged from 27% to 66%.

OPTIMA, the largest trial in the analysis, found patients maintained a stable low disease activity

target on initial methotrexate plus adalimumab, even after withdrawal of the biologic. After a year of methotrexate maintenance treatment, the remission rate was significantly higher in patients started on the combination than on monotherapy (27% versus 15%, P<0.0001).

Commenting on the meta-analysis for MedPage Today, Dallas-based rheumatologist Scott J. Zashin, MD, said, "While the data are of interest, the data should be interpreted with caution." He cited the small number of studies included, the differing study protocols, and the varying dosages of methotrexate.

"And because of the cost of biologics, many insurance companies that pay for medications in the U.S. require patients to have failed methotrexate or similar drugs before they will agree to pay for biologics," Zashin added. "If clinical studies could show that combination treatment used as a first-line therapy could not only improve disease outcome but also decrease the need for maintenance treatment with expensive biologics, the paradigm might shift."

The authors recommended that future trials test the subcutaneous administration of methotrexate since recent findings suggest this route is associated with greater clinical efficacy than oral even at an identical dosage of 15 mg/week.

Among the limitations of the current analysis study, the authors noted, is the small number of studies qualifying for inclusion

and the resulting reduced power to detect heterogeneity and publication bias. In addition, the generalizability of results from randomized trials may be limited since the carefully selected eligible participants were less diverse than those in daily practice. All patients in this study, for example, were DMARD-naive and had very high disease activity levels. Also, with the study's maximum follow-up of 76 weeks, it was unclear whether remission was sustained permanently.

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